The high risk follow-up study of offspring of bipolar (manic-depressive) parents is in its 3rd year. Five of 53 subjects have developed major affective disorder (as compared with 0/38 controls). The index subjects have increased scores on the disinhibition subscale of Zucherman's Sensation Seeking Scale. We have completed a family study of rapid cycling bipolar patients. Relatives of rapid cyclers may have a lower morbid risk of major affective disorder. Initial data analysis suggests that non-genetic factors contribute to the etiology of this affective subtype. Studies of CSF neuropeptides have continued. Neuropeptide Y levels were not altered in subjects with Alzheimer's disease, schizophrenia or eating disorders. Growth hormone releasing factor and atrial naturietic factor were not different in bipolar patients compared to controls. Sixteen neuropeptides, neurotransmitters and metabolites were measured in the same persons at different times and 14/16 were found to be stable. Physostigmine infusions were done in an effort to provoke release of vasoactive intestinal polypeptide into CSF but this was not successful. Steroid treatment was found to lower cerebrospinal fluid beta endorphin and beta lipotropin. Computerized tomographic scans have been measured to assess ventricular size in 59 bipolar subjects and 16 controls. Frontal horn measurements are not different in the two groups. Correlation of ventricular size with familial risk of affective illness and lithium response is continuing.